Background: GP is the standard first-line chemotherapy for R/M NPC. However, the outcome of patients who are refractory to first-line chemotherapy is poor. There remains an unmet need for more effective first-line treatment. Overexpression of vascular endothelial growth factor (VEGF) is common in NPC and the higher expression is related to lower OS. This feature makes NPC potentially suitable for antiangiogenic treatment. Anlotinib is a novel multitarget tyrosine kinase inhibitor that targets VEGFR 1 to 3, fibroblast growth factor receptor 1 to 4, and platelet-derived growth factor receptor α and β. Our phase I study of anlotinib in R/M NPC patients who failed from standard treatment had shown a manageable safety profile and promising antitumor activity with an ORR of 25%. This phase 3 trial aims to compare the efficacy and safety of anlotinib versus placebo in combination with GP in patients with R/M NPC in the first-line setting. Methods: Key eligibility criteria of this study are that the patient has metastatic disease after curative radiotherapy, or is primarily metastatic; has an ECOG PS of 0 or 1; has adequate organ function; and has at least 1 measurable lesion according to RECIST 1.1. Eligible patients will be randomized in a 1:1 ratio to receive intravenous gemcitabine at 1 g/m² on days 1 and 8, cisplatin at 75 mg/m² on day 1, plus anlotinib or placebo 12 mg daily orally on days 1–14 every 3 weeks for a maximum of 6 cycles followed by anlotinib or placebo 12 mg daily on days 1–14 every 3 weeks as maintenance therapy. The primary endpoint is PFS. Secondary endpoints include OS, ORR, quality of life and safety profile. Independent Data Monitoring Committee and Independent Review Committee will be used in this study. We assume that the median PFS will be 10 mos in anlotinib group and 7 mos in placebo group. To detect a 3-month improvement of PFS in anlotinib group at a two-sided significant level of 0.05 and power of 0.8, allowing for a dropout rate of 10%, a total of 336 patients will be enrolled. From August 2018, 58 patients have been enrolled. Clinical trial information: NCT03601975